A useful therapeutic method for the treatment of malignancies is the administration of compounds that stimulate the differentiation of malignant cells to normal cells, thereby inhibiting and/or reversing the malignant transformation. Thus, it has been shown by Suda et al (U. S. Pat. No. 4,391,802) that 1.alpha.-hydroxyvitamin D compounds (e.g. specifically 1.alpha.,25-dihydroxyvitamin D.sub.3 and 1.alpha.-hydroxyvitamin D.sub.3) possess, for example, potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to non-malignant macrophages (monocytes). Hence, these compounds are useful for the treatment of certain malignancies, and specifically for the treatment of leukemia (Suda et al., U.S. Pat. No. 4,391,802). When used for such treatment, however, these known 1.alpha.-hydroxyvitamin D compounds have the disadvantage that they are also very potent calcemic agents, i.e. they cause elevated blood calcium levels by stimulating intestinal calcium absorption and bone calcium resorption. This calcemic activity represents the well known classical function of these compounds. Furthermore, the cell differentiation activity (and, hence, anti-leukemic activity) of these compounds correlates with their calcemic activity. For example, 1, 25-dihydroxyvitamin D.sub.3, the most potent compound in inducing the differentiation of malignant cells to macrophages, is also the most potent vitamin D metabolite in stimulating calcium transport or raising serum calcium levels. For practical use a cell-differentiating agents, this potent calcemic activity is, of course, an undesired side effect, since the doses required for efficacy in differentiating malignant cells can lead to excessively high and non-physiological serum calcium levels in the treated subjects.
A novel class of secosterol compounds has also been prepared (U.S. Pat. No. 4,940,700) which exhibit high differentiation activity towards malignant cells, such as leukemia cells, but do not have the undesired side effects (potent calcemic action) of some of the known compounds mentioned above. This selectivity and specificity of action makes the secosterols useful and preferred agents for the treatment of malignancies such as leukemia.
This class of secosterols is characterized by the general structures I and II shown below: ##STR1## where R is methyl, ethyl or propyl and where each of X.sup.1 and X.sup.2 represent, independently, hydrogen or an acyl group.
Purely structurally, this class of secosterols has similarity with some of the known vitamin D compounds. Unlike the known vitamin D compounds, however, the secosterols do not express the classic vitamin D activities in vivo, i.e. stimulation of intestinal calcium transport, or the mobilization of bone calcium, and hence they cannot be classified as vitamin D derivatives from the functional point of view. These secosterols are remarkably effective in inducing the differentiation of leukemia cells to normal (non-malignant) macrophages, since, as mentioned above, potent cell differentiation activity among the known vitamin D-related compounds was always closely correlated with potent calcemic activity. Thus, the secosterols overcome the shortcomings of the known vitamin D-related anti-leukemic agents mentioned above, and can be considered preferred agents for the control and treatment of malignant diseases such as leukemia. This finding provides an effective method for the treatment of malignancies, since the above described secosterols, and preferably 1.alpha.-hydroxy-homopregnacalciferol, i.e. the secosterol of general structure I where R is methyl and X.sub.1 and X.sub.2 are both hydrogen, can be administered to subjects in doses sufficient to cause differentiation of malignant cells to normal cells, without producing simultaneously unphysiologically high and deleterious blood calcium levels.
A related substance, 1.alpha.-hydroxypregnacalciferol, has been prepared by Lam et al. [Steroids 26, 422 (2975)]. It should be noted that in addition to the novel synthesis disclosed herein, the secosterols of structures I and II, where R is methyl, ethyl or propyl, can also be prepared according to the general process illustrated in U.S. Pat. No. 4,940,700. Suitable starting materials for the process disclosed in U.S. Pat. No. 4,940,700 are i-ether steroids where, depending on the final product desired, R may be methyl, ethyl or propyl.